Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten containing grains (i.e.;wheat, barley, and rye) in genetically susceptible individuals. Given the undisputable role of gliadin in causing inflammation and autoimmunity, CD represents a unique model of autoimmune disorder for which, in contrast to most other autoimmune diseases, the triggering environmental factor (gliadin), a close genetic association with HLA genes (DQ2 or DQ8), and a highly specific humoral autoimmune response (auto-antibodies to tissue transglutaminase) are known. However, despite the significant progress made in understanding the adaptive immunological aspects of CD pathogenesis, the early steps following intestinal mucosal exposure to gliadin leading to the loss of tolerance and the development of the autoimmune process are still largely unknown. Increasing evidence in literature seem to suggest a dysfunctional cross talk between innate and adaptive immunity as the key pathogenic element in the autoimmune process of the disease. Recent retrospective studies also suggest that this dysfunctional cross talk is influenced by the timing of gluten introduction in the diet of subjects genetically susceptible to CD. Therefore, we propose to investigate this aspect of CD pathogenesis in a blend of basic and applied studies, which will yield fundamental insights into the role of timing of gluten introduction in early steps involved in the onset of the disease. Our overall hypothesis is that the timing of introduction of gluten-containing cereals into the diet of infants genetically at risk for CD may influence the loss of tolerance to the protein and subsequent activation of the adaptive immune system causing the intestinal and extra-intestinal inflammation typical of the disease. We will take full advantage of a very conducive environment (that includes the Mucosal Biology Research Center and the Center for Celiac Research at the University of Maryland) thematically relevant to this proposal. Our long-term objective is to capitalize on the unique features of CD as an autoimmune disorder to gain insights on the role of the timing of gluten exposure in dictating loss of intestinal tolerance to the protein and possibly to other non-self antigens leading to CD and other autoimmune disorders associated with CD. PUBLIC HEALTH RELEVANCE Increasing evidence in literature seems to suggest a dysfunctional cross talk between innate and adaptive immunity as the key pathogenic element in the autoimmune process of celiac disease (CD). Several retrospective studies have suggested that the time of gluten introduction in the diet of infants at risk for CD may affect the incidence of the disease. However, the data supporting this hypothesis are circumstantial, limited by their retrospective design, and often criticized by alternative interpretations suggesting that the delay in gluten exposure merely postpones the onset of symptoms rather than preventing the disease. In order to address this issue in a more rigorous manner, with this application we propose to perform a prospective, randomised, double-blind dietary intervention study to establish the relationship between age of gluten introduction and development of CD autoimmunity in at-risk infants. By investigating the role of infant nutrition (early vs late exposure to dietary gluten) this project will contribute to clarify the early pathophysiological changes that may lead to CD development. The consequent implementation of strategies of primary prevention of CD in the general pediatric population could significantly reduce the costs associated with the diagnosis and treatment of this life-long disorder.